Pyrrolobenzodiazepines as key intermediates in the synthesis of dimeric cytotoxic pyrrolobenzodiazepines

A method of synthesizing a compound of formula Ia or Ib:

• from a compound of formula IIa or IIb respectively:
• comprising deprotecting a C7 or C8 hydroxyl moiety, wherein:
• the dotted lines indicates the optional presence of a double bond between C1 and C2 or C2 and C3;
• R2 and R3 are independently selected from —H, ═O, ═CH2, —CN, —R, OR, halo, ═CH—R, O—SO2—R, CO2R and COR;
• R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;
• where R and R′ are independently selected from optionally substituted C1-12 alkyl, heterocyclyl groups having 3 to 20 ring atoms of which 1 to 10 are heteroatoms independently selected from the group consisting of N, O and S and aryl or heteroaryl groups having 5 to 20 ring atoms, the heteroaryl groups having one or more heteroatoms independently selected from the group consisting of N, O and S, wherein the optional substituents are independently selected from halo, hydroxy, ether, alkoxy, acetal, hemiacetal, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy, thiocarboxy, thiolcarboxy, thionocarboxy, imidic acid, hydroxamic acid, ester, acyloxy, oxycaroyloxy, amino, amido, thioamido, acylamido, aminocaronyloxy, ureido, guanidino, tetrazolyl, amidino, nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano, isothiocyano, sulfhydryl, disulfide, sulfine, sulfonyl, sulfino, sulfo, sulfinate, sulfonate, sulfinyloxy, sulfonyloxy, sulfate, sulfamyl, sulfonamido, sulfamino, sulfonamino, sulfinamino, phosphino, phosphor, phosphinyl, phosphono, phosphonate, phosphonooxy, phosphate, phosphorous acid, phosphite, phosphoramidite, or phosphoramidate;
• RA is selected from H, R, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;
• R10 is a carbamate-based nitrogen protecting group;
• R11 is an oxygen protecting group;
• and
• R14 is an oxygen protecting group orthogonal to R11.

A method of synthesising a compound of formula IIIa or IIIb:

• from a compound of formula Ia or Ib respectively:
• wherein:
• the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3;
• R2 and R3 are independently selected from —H, ═O, ═CH2, —CN, —R, OR, halo, ═CH—R, O—SO2—R, CO2R and COR;
• R6, R9, R12 and R13 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;
• where R and R′ are independently selected from optionally substituted C1-12 alkyl, heterocyclyl groups having 3 to 20 ring atoms of which 1 to 10 are heteroatoms independently selected from the group consisting of N, O and S and aryl or heteroaryl groups having 5 to 20 ring atoms, the heteroaryl groups having one or more heteroatoms independently selected from the group consisting of N, O and S, wherein the optional substituents are independently selected from halo, hydroxy, ether, alkoxy, acetal, hemiacetal, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy, thiocarboxy, thiolcarboxy, thionocarboxy, imidic acid, hydroxamic acid, ester, acyloxy, oxycaroyloxy, amino, amido, thioamido, acylamido, aminocaronyloxy, ureido, guanidino, tetrazolyl, amidino, nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano, isothiocyano, sulfhydryl, disulfide, sulfine, sulfonyl, sulfino, sulfo, sulfinate, sulfonate, sulfinyloxy, sulfonyloxy, sulfate, sulfamyl, sulfonamido, sulfamino, sulfonamino, sulfinamino, phosphino, phosphor, phosphinyl, phosphono, phosphonate, phosphonooxy, phosphate, phosphorous acid, phosphite, phosphoramidite, or phosphoramidate;
• RA is selected from H, R, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;
• R10 is a carbamate-based nitrogen protecting group and R15 is either O—R11, wherein R11 is an oxygen protecting group, or OH, or R10 and R15 together form a double bond between N10 and C11;
• and
• where R″is a C3-12 alkylene group, and each X is O;
• and R2′, R3′, R6′, R9′, R10′, R12′, R13′ and R15′ are all independently selected from the same lists as previously defined for R2, R3, R6, R9, R10, R12, R13 and R15 respectively, comprising either:
• (a) reacting a compound of formula Ia or Ib with a compound having the formula Y—R″—Y′ to yield a compound of formula IIIa or IIIb;
• or
• (b) (i) reacting a compound of formula Ia or Ib with a compound having the formula Y—R″— YProt, and
• (ii) converting YProt in the reaction product from (i) to Y′, and
• (iii) reacting the product from (ii) with a compound of formula Ia or Ib to yield a compound of formula IIIa or IIIb;
• wherein:
• Y, Y′ are independently selected from OH, I, Br, Cl, mesylate or tosylate;
• YProt is a precursor to Y′ or a chemically protected form of Y′ having a protecting group that is orthogonal to R10 and R11.